Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Vanner RJ, Remke M, Gallo M, Selvadurai HJ, Coutinho F, Lee L, et al. Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. Cancer Cell 2014;26:33–47.Vanner and colleagues characterize the biology of progenitor cells within the SHH subgroup of medulloblastoma. They show in a mouse model that SOX2 is expressed only in quiescent tumor-propagating cells, which comprise a small proportion of the tumor cell mass. Lineage tracing revealed that a substantial proportion of murine SHH medulloblastoma was derived from SOX2-expressing cells. Clinically relevant therapies decreased overall proliferation but were relatively ineffective against the SOX2high, tumor-propagating subpopulation; however mithramycin, which crosses the blood–brain barrier, was potentially effective. Genes upregulated in multiple quiescent stem cell populations were highly enriched in SOX2-expressing cells. This gene signature was correlated with poor prognosis in patients with medulloblastoma. This article elegantly outlines roles for tumor-propagating cells in SHH-driven medulloblastoma and identifies a marker for therapy resistance.Li B, Fei DL, Flaveny CA, Dahmane N, Baubet V, Wang Z, et al. Pyrvinium attenuates Hedgehog signaling downstream of Smoothened. Cancer Res; Published OnlineFirst July 3, 2014; doi:10.1158/0008-5472.CAN-14-0317.Li and colleagues previously identified the FDA-approved anti-pinworm drug pyrvinium as a potent casein kinase 1α (CK1α, CSNK1A1) agonist. They now show that pyrvinium potently inhibits Hedgehog (HH) signaling by reducing the stability of the GLI family of transcription factors, the most distal components of HH signaling. Of importance, pyrvinium inhibits the activity of a vismodegib-resistant SMO mutant as well as GLI activity resulting from loss of the negative regulator Suppressor of fused (SUFU), or overexpression of a GLI protein, suggesting potential clinical relevance (following formulation and/or optimization of delivery route). Additionally, pyrvinium is an allosteric activator of CK1α. Drugs that act via allosteric mechanisms are not constrained by active site chemistry and are more selective in their mode of action. Finally, using in vitro and in vivo studies, the authors demonstrate that pyrvinium attenuates growth of medulloblastoma, an HH-dependent cancer, and reduces the expression of HH biomarkers.Hudak JE, Canham SM, Bertozzi CR. Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion. Nat Chem Biol 2014;10:69–75.By functionalizing the cell surface with glycopolymers and exposing cells to freshly isolated human PBMCs and NK cells, Hudak and colleagues were able to identify sialylated epitopes that regulate cell-mediated NK cell activation, also identifying a potential resistance mechanism. Among a panel of glycopolymers, the monosaccharide sialic acid (Sial polymer) strongly protected against cell killing. This protection was dependent on NK cell surface expression of SIGLEC7, a sialic acid–binding immunoglobulin-like lectin surface receptor, as antibodies against SIGLEC7 abrogated the inhibitory effect. Upon binding to the sialic acid polymer, SIGLEC7 colocalized with the phosphatase SHP1 (PTPN6) to the immune cell synapse, dampening NK cell–promoted cytotoxicity. In hypersialylated breast adenocarcinoma, gastric carcinoma, and Burkitt cell lines, the Sial polymer also abrogated antibody-dependent killing by NK cells. Thus, sialic acid on cancer cells promotes an inhibitory signal to dampen NK cell–promoted cytotoxicity, contributing to immune evasion.Pradeep S, Kim SW, Wu SY, Nishimura M, Chaluvally-Raghavan P, Miyake T, et al. Hematogenous metastasis of ovarian cancer: rethinking mode of spread. Cancer Cell 2014;26:77–91.Ovarian cancer metastasis to the omentum has always been thought to follow an intraperitoneal route. Pradeep and colleagues found abundant circulating cancer cells in patients with ovarian cancer and numerous disseminated tumor cells lodged in the omental vasculature, supporting an argument for an alternative route to this preferred site of metastasis. This study shows that ERBB3-positive ovarian cancer cells disseminate hematogenously and preferentially colonize and expand in the omentum due to the presence of neuregulin1 (NRG1), a ligand for ERBB3 in that microenvironment. These findings shift a long-standing paradigm in ovarian cancer metastasis and provide new therapeutic targets for ovarian cancer metastasis, which for the most part is incurable.Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK. Novel somatic and germline mutations in intracranial germ cell tumors. Nature 2014;511:241–5.The biology of intracranial germ cell tumors (IGCT) is largely unknown. Wang and colleagues conducted an in-depth analysis of 62 such cases and identified novel somatic mutations in genes involved in KIT/RAS or AKT/mTOR pathways, the majority of which are predicted to be deleterious and were mutually exclusive with KIT mutations previously reported in a subset of pure germinomas. Recurrent somatic mutations were also identified in CBL, BCORL1, MTOR, TP53, SPTA1, KDM2A, and LAMA4. The investigators also identified functional germline variants in JMJD1C, which functions as a chromatin modifier gene and has a reported role in germinal tissue development. Interestingly, these variants are enriched in IGCT patients in Japan, where there is a significantly higher incidence. The genetic alterations identified in this study suggest potentially promising targets for development of new treatment strategies.Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, et al. Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature 2014 Jul 9. doi: 10.1038/nature13473. [Epub ahead of print].Whereas MYC enhances expression of many genes during normal mitogenesis, MYC-driven tumor cells elaborate a distinct subset of differentially expressed genes. Walz and colleagues explore how MYC functions to reshape this oncogenic transcriptome through inducible expression and depletion of MYC in various cellular contexts. Their results suggest that MYC activates or represses specific sets of direct target genes, primarily through promoters containing noncanonical weak-affinity MYC binding sites. While both MYC and MIZ1 (ZBTB17) act on their own as transcriptional activators, the MYC/MIZ1 complex represses target genes. Thus, increased MYC expression changes the ratio of MYC to MIZ1, allowing increased levels of MYC to attenuate the expression of a subset of direct target genes. The differential transcriptional response in normal versus oncogenic cells might be harnessed to target MYC-dependent tumors.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.